High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias
High-throughput screening for fatty acid uptake inhibitors in humanized yeast identifies atypical antipsychotic drugs that cause dyslipidemias
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DOI：
10.1194/jlr.d700015-jlr200
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发表时间：
2008-01-01
影响因子：
6.5
通讯作者：
DiRusso, Concetta C.
中科院分区：
文献类型：
--
作者：
Li, Hong;Black, Paul N.;DiRusso, Concetta C.
脂肪酸与血脂异常的发展有关，导致2型糖尿病和心血管疾病。我们使用标准化的小化合物文库筛选人源化酵母，以确定抑制脂肪酸转运蛋白（FATP）介导的脂肪酸摄取进入细胞的化合物。该筛选程序使用表达人类FATP2的活酵母细胞来鉴定减少荧光脂肪酸类似物4,4-二氟-5-甲基-4-硼-3a， 4-二氮-s-吲哚烯-3-十二烷酸（C-1-BODIPY-C-12）进口的小化合物。所使用的文库包括2,080种已知具有生物活性的化合物。其中，细胞相关C-1-BODIPY-C-12荧光减少1.8%，被选为人类fatp2介导的脂肪酸摄取的潜在抑制剂。在二次筛选的基础上，筛选出28个化合物作为潜在的脂肪酸摄取抑制剂。有些化合物可分为四类，具有相似的结构特征。最大的一组在结构上与用于治疗精神分裂症和相关精神疾病的三环吩噻嗪衍生药物家族相关，这些药物也已知会引起代谢副作用，包括高甘油三酯血症。研究了潜在靶向化合物与人FATP相互作用的特异性和对人Caco-2细胞的作用。
Fatty acids are implicated in the development of dyslipidemias, leading to type 2 diabetes and cardiovascular disease. We used a standardized small compound library to screen humanized yeast to identify compounds that inhibit fatty acid transport protein (FATP)-mediated fatty acid uptake into cells. This screening procedure used live yeast cells expressing human FATP2 to identify small compounds that reduced the import of a fluorescent fatty acid analog, 4,4-difluoro-5-methyl-4-bora-3a, 4a-diaza-s-indacene-3-dodecanoic acid (C-1-BODIPY-C-12). The library used consisted of 2,080 compounds with known biological activities. Of these, similar to 1.8% reduced cell-associated C-1-BODIPY-C-12 fluorescence and were selected as potential inhibitors of human FATP2-mediated fatty acid uptake. Based on secondary screens, 28 compounds were selected as potential fatty acid uptake inhibitors. Some compounds fell into four groups with similar structural features. The largest group was structurally related to a family of tricyclic, phenothiazine-derived drugs used to treat schizophrenia and related psychiatric disorders, which are also known to cause metabolic side effects, including hypertriglyceridemia. Potential hit compounds were studied for specificity of interaction with human FATP and efficacy in human Caco-2 cells.